Dual HER2 Blockade Superior for PFS in HER2+/HR+ Metastatic Breast Cancer

Stephen R.D. Johnston, PhD

The combination of lapatinib (Tykerb), trastuzumab (Herceptin), and an aromatase inhibitor (AI) reduced the risk for death or progression by 38% in women with HER2+/HR+ metastatic breast cancer (MBC) compared with those treated with a targeted agent plus AI, according to findings published in the Journal of Clinical Oncology.

Median progression-free survival (PFS) in the phase III ALTERNATIVE trial was 11 months for the triplet versus 5.7 months for women assigned to trastuzumab plus AI (HR, 0.62; 95% CI, 0.45-0.88; P = .0064). Median PFS also favored the triplet compared to trastuzumab plus AI (8.3 vs 5.7 months; HR, 0.71; 95% CI, 0.51-0.98; P = .0361). Investigators reported that overall response rate (ORR), clinical benefit rate, and overall survival (OS) all favored the experimental regimen.

“The PFS benefit obtained with lapatinib plus trastuzumab plus AI in patients with HER2-positive, HR-positive MBC who had been previously treated with trastuzumab and endocrine therapy is clinically meaningful and robust,” corresponding author Stephen R.D. Johnston, PhD, The Royal Marsden NHS Foundation Trust, and coinvestigators wrote.

“The ALTERNATIVE trial showed relevant clinical benefit with a relatively good tolerability, supporting that patients with HER2-positive/HR-positive MBC who are not candidates for chemotherapy can be adequately treated with dual HER2 blockade (lapatinib + trastuzumab) plus an AI. This combination can potentially offer an effective and well-tolerated, chemotherapy-sparing alternative treatment regimen for patients for whom chemotherapy is not intended.”

Investigators in the open-label trial recruited 355 postmenopausal women with histologically or cytologically confirmed ER+ and/or HR+, HER2+ MBC at 112 medical centers in 29 countries. Eligible patients had undergone prior endocrine therapy and experienced disease progression during or after a prior regimen containing trastuzumab plus chemotherapy in the adjuvant or neoadjuvant setting and/or in the first-line metastatic setting.

Patients with either measurable or nonmeasurable disease per RECIST v1.1, ECOG performance status 0 or 1, adequate baseline organ function, and no active or history of cardiac disease were eligible. Patients for whom chemotherapy was intended per investigator’s judgement were excluded.

Patients were assigned to lapatinib plus trastuzumab plus AI (n = 120), trastuzumab plus AI (n = 117), or lapatinib plus AI (n = 118). Patients self-administered 1000 mg of oral lapatinib per day in the triplet arm and 1500 mg per day in the lapatinib plus AI arm. Trastuzumab was administered at a loading dose of 8 mg/kg, followed by the maintenance dose of 6 mg/kg every 3 weeks in both trastuzumab arms. Investigator’s choice of oral AIs included 2.5 mg of letrozole per day, 1 mg of anastrozole per day, or 25 mg of exemestane per day.

Investigators conducted the PFS analysis in the intent-to-treat (ITT) population after 137 events.

The dual HER2 blockade plus AI combination was associated with a consistent PFS benefit in patients with measurable disease, patients treated with steroidal or nonsteroidal AIs, and patients receiving prior trastuzumab in a neoadjuvant or metastatic setting. Cox regression analysis showed that the PFS benefit with the combination was consistent with the primary analysis (HR, 0.56; 95% CI, 0.394-0.794). A consistent PFS benefit with the triplet was observed in the centrally confirmed HER2-positive subpopulation.

The PFS benefit associated with lapatinib plus trastuzumab plus AI was also observed in the centrally confirmed HER2+/HR+ subpopulation (HR, 0.73; 95% CI, 0.43-1.24).

ORR was superior in dual HER2 blockade group (31.7%) compared with trastuzumab plus AI (13.7%) and lapatinib plus AI (18.6%). Similarly, median duration of response favored the lapatinib/trastuzumab arm (13.9 months) versus trastuzumab/AI (8.3 months), and lapatinib/AI (11.1 months).

OS data were immature at the time of this analysis but trended in favor of dual HER2 blockade plus AI versus trastuzumab plus AI (median OS, 46.0 vs 40.0 months; HR, 0.60; 95% CI, 0.35-1.04). The median OS was 45.1 months for lapatinib plus AI.

The most common any-grade adverse event (AE) in the triplet arm was diarrhea (69%), followed by rash (36%), nausea (22%), and paronychia (30%). Investigators reported that the frequency of grade 3/4 AEs was <5% across the 3 treatment arms except for diarrhea in the lapatinib/trastuzumab plus AI arm (13%) and the lapatinib plus AI arm (6%).

Johnston SRD, Hegg R, Im S, et al. Phase III, Randomized study of dual human epidermal growth factor receptor 2 (her2) blockade with lapatinib plus trastuzumab in combination with an aromatase inhibitor in postmenopausal women with her2-positive, hormone receptor—positive metastatic breast cancer: ALTERNATIVE [published online December 15, 2017]. J Clin Oncol doi: 10.1200/JCO. 2017.74.7824.